US4728659A - Aminomethyl derivatives and preparation process thereof as well as platelet aggregation inhibitors containing same - Google Patents
Aminomethyl derivatives and preparation process thereof as well as platelet aggregation inhibitors containing same Download PDFInfo
- Publication number
- US4728659A US4728659A US06/748,686 US74868685A US4728659A US 4728659 A US4728659 A US 4728659A US 74868685 A US74868685 A US 74868685A US 4728659 A US4728659 A US 4728659A
- Authority
- US
- United States
- Prior art keywords
- sub
- group
- platelet aggregation
- aminomethyl
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Definitions
- This invention relates to novel aminomethyl derivatives, and more specifically to aminomethyl derivatives having strong platelet aggregation inhibitory effects and their acid addition salts, and preparation process thereof as well as platelet aggregation inhibitors containing same.
- the present inventors have synthesized a variety of compounds and investigated their pharmacological effects. In the course of the investigation, it has been found that certain specific aminomethyl derivatives have excellent platelet aggregation inhibitory effects and are hence useful for thrombus-inducing diseases of circulatory organs, leading to completion of this invention.
- the first object of this invention is to provide an aminomethyl derivative of the following general formula (I): ##STR5## wherein A represents a group --C.tbd.C-- or --CH ⁇ CH--, Y represents a group ##STR6## (in which R 3 being a lower alkyl or alkoxy group or a halogen atom) or ##STR7## (in which R 4 being a hydrogen atom or R 3 ), and R 1 and R 2 represent individually a lower alkyl group, with a proviso that Y is other than the group ##STR8## when A means the group --CH ⁇ CH--.
- the second object of this invention is to provide a process for preparing the aminomethyl derivative represented by the general formula (I).
- the third object of this invention is to provide a platelet aggregation inhibitor comprising the aminomethyl derivative.
- novel aminomethyl derivatives (I) of this invention may be divided roughly into the following two groups of compounds (Ia) and (Ib): ##STR9## wherein A, R 1 , R 2 , R 3 and R 4 have the same meanings as defined above.
- the compounds of the formula (Ia) are derivatives of the so-called butynophenone. Reported earlier work on such butynophenone derivatives is limited to compounds of the above general formula (I) in which R 3 is a hydrogen atom and R 1 and R 2 mean individually an ethyl group [Zh. Org. Khim. 11, 2311-5 (1975)]. However, their pharmacological effects have not been known to all to date.
- the compounds represented by the general formula (Ia) may, for example, be prepared in accordance with the below-described reaction scheme. Incidentally, it is also possible to prepare, in the same manner, the above-mentioned compounds of the general formula (Ia) in which R 3 represents a hydrogen atom and R 1 and R 2 represents individually a lower alkyl group which may include an ethyl group.
- R 3 represents a hydrogen atom
- R 1 and R 2 represents individually a lower alkyl group which may include an ethyl group.
- X represents a magnesium halide or alkali metal
- R 1 , R 2 and R 3 have the same meaning as defined above.
- the intended aminomethyl derivative (Ia) is prepared by reacting a benzaldehyde derivative represented by the general formula (II) with a metal compound of propargyl amine derivative represented by the general formula (III) or reacting an ⁇ -phenyl propargyl alcohol derivativere presented by the general formula (IV) with formaldehyde and a secondary amine derivative represented by the general formula (V) to obtain an alkynolamine derivative represented by the general formula (VI) and then oxidizing the alkynol amine derivative with an oxidizing agent such as manganese dioxide or the like.
- an oxidizing agent such as manganese dioxide or the like.
- the reaction for obtaining the compound (VI) from the compound (II) and the compound (III) may be practiced by stirring, at room temperature, the compound (II) and compound (III) or causing them to reflux for several hours in a solvent inert to the reaction.
- a solvent inert As the solvent, ether, tetrahydrofuran or the like may be employed.
- the reaction for obtaining the compound (VI) from the compound (IV), formaldehyde and the compound (V) is the so-called Mannich reaction.
- This reaction may be practiced by mixing the above starting raw materials and then stirring the resultant mixture for several hours in the range of from room temperature to 60°-70° C.
- a solvent for the reaction may be employed water, methanol, ethanol, dioxane or the like.
- the thus-obtained compound (VI) is further subjected to an oxidation reaction, thereby obtaining the intended compound (Ia).
- the oxidation may be effected by a method known per se in the art. For example, it may be effected by adding the compound (VI) and an oxidizing agent such as manganese dioxide or the like to a solvent inert to the reaction, such as methylene chloride, chloroform, carbon tetrachloride, acetone, benzene or the like and then mixing them at room temperature for several hours.
- the compounds represented by the formula (Ib) may be prepared, for example, in accordance with the following reaction equation: ##STR11## wherein R 1 , R 2 , R 4 and A have the same meaning as defined above.
- the intended aminomethyl derivative (Ib) may be prepared by reacting an alkynolamine or alkenolamine represented by the general formula (VII) with nicotinic acid (VIII) or its reactive derivative.
- the reactive derivative of nicotinic acid may be mentioned for example an acid halogenide, acid anhydride, mixed acid anhydride, ester or the like.
- a reactive derivative of nicotinic acid (VIII) it is preferred to conduct the reaction in the presence of pyridine, a tertiary amine such as trimethylamine or triethylamine, or an deoxidizer such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide or sodium hydroxide.
- This reaction may be practiced by stirring, at room temperature, the reactants or causing them to reflux for several hours in a suitable solvent, for example in a solvent inert to the reaction such as tetrahydrofuran, benzene, toluene, acetone or methyl ethyl ketone.
- a suitable solvent for example in a solvent inert to the reaction such as tetrahydrofuran, benzene, toluene, acetone or methyl ethyl ketone.
- reaction it is preferred to conduct the reaction in the presence of a 2-halo-1-alkylpyridinium salt and pyridine or a tertiary amine such as triethylamine or tributylamine, or in the presence of diethyl azodicarboxylate and triphenylphosphine as condensing agents. It is preferred to conduct this reaction in a solvent inert to the reaction.
- a solvent may be mentioned ether, tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, or the like.
- the thus-obtained aminomethyl derivative (I) of this invention may be converted, if necessary, into an inorganic salt such as hydrochloride, hydrobromide or sulfate or an organic salt such as maleate, fumarate, tartrate, citrate or methanesulfonate.
- an inorganic salt such as hydrochloride, hydrobromide or sulfate
- an organic salt such as maleate, fumarate, tartrate, citrate or methanesulfonate.
- the compound (I) contains both cis- and trans-isomers. Both of these isomers are included in the present invention.
- the compounds of this invention exhibited strong inhibitory effects against aggregation of platelets by ADP and against aggregation of platelets by arachidonic acid.
- Each sample compound was orally administered at 30 mg/Kg to a male Wister rat (body weight: 220 g) which had fasted for 24 hours.
- Platelet-rich plasma was obtained from blood which had been collected 2 hours after the administration and added with sodium citrate. Changes in platelet aggregation upon addition of 60 ⁇ M of ADP or 100 ⁇ g/ml of collagen were observed. The number of platelets was adjusted to 6 ⁇ 10 5 platelets/mm 3 for aggregation by ADP and to 3 ⁇ 10 5 platelets/mm 3 for aggregation by collagen.
- Each of the sample compounds was dissolved in DMSO+Tween 80 (trade mark) prior to its administration. Test results are given in Table 2.
- the compounds of this invention showed strong inhibitory effects against aggregation of platelets by ADP and against aggregation of platelets by collagen.
- each of certain sample compounds (which had been obtained in Examples 6, 7, 10 and 15-17, which will be given herein) was dissolved in water and was then administered intraperitoneally at a dose of 200 mg/Kg to a group of five ddY male mice. Those mice were fed for 7 days while observing them. Even after the elapsed time of 7 days, all the mice were still alive and no abnormality was observed thereon. Therefore, the LD 50 of each of the sample compounds is greater than 200 mg/Kg.
- the aminomethyl derivatives (I) of this invention may be administered either orally or parenterally.
- the platelet aggregation inhibitors of this invention may be formed into various preparation forms depending on their ways of administration, for example, into orally-dosable preparation forms such as powders, tablets, capsules, granules, liquid preparations and the like; and parenterally-dosable preparation forms such as subcutaneously-injectable solutions, intramuscularly-injectable solutions and intravenously-injectable solutions, preparations suitable for admixture with transfusional solutions, ointments, tinctures, plasters, suppositories, etc.
- the aminomethyl derivatives (I) may be combined and processed suitably with an excipient such as starch, lactose, mannitol or the like; a binder such as sodium carboxymethyl cellulose, hydroxypropyl cellulose or the like; a disintegrator such as crystalline cellulose, calcium carboxymethyl cellulose or the like; a lubricant such as talc, magnesium stearate or the like; a fluidity improver such as light silicic anhydride; and/or the like, thereby to produce powders, tablets, capsules or granules.
- an excipient such as starch, lactose, mannitol or the like
- a binder such as sodium carboxymethyl cellulose, hydroxypropyl cellulose or the like
- a disintegrator such as crystalline cellulose, calcium carboxymethyl cellulose or the like
- a lubricant such as talc, magnesium stearate or the like
- a fluidity improver such as light silicic
- salts of the aminomethyl derivatives (I) of this invention for example, their hydrochlorides are soluble in aqueous solvents such as water, physiological saline and the like, it is possible to produce aqueous liquid preparations, injectable aqueous preparations, etc.
- the thus-prepared platelet aggregation inhibitors of this invention may be administered to adults, generally, at daily doses of 0.02-100 mg/Kg in terms of their aminomethyl derivatives (I) when administered orally or at doses of 0.01-50 mg/Kg in terms of their aminomethyl derivatives (I) when administered perenterally. It is suitable to administer these doses by dividing them into 1 to several portions a day.
- the aminomethyl derivatives (I) of this invention have excellent platelet aggregation inhibitory effects and their safety levels are also high, they are effective, as platelet aggregation inhibitors, for the treatment and prevention of various diseases induced by the formation of thrombi, for example, venous thrombosis, coronary thrombosis in cardiac infarction, pulmonary embolism, cerebral thrombosis and embolism, etc.
- the total weight was adjusted to 200 mg with lactose.
- the total weight was adjusted to 205 mg with lactose.
- an injectable preparation was produced with the following composition.
Abstract
Disclosed herein are aminomethyl derivatives each of which is of the following general formula (I): ##STR1## wherein A represents a group --C.tbd.C-- or --CH═CH--, Y represents a group ##STR2## (in which R3 being a lower alkyl or alkoxy group or a halogen atom) or ##STR3## (in which R4 being a hydrogen atom or R3), and R1 and R2 represent individually a lower alkyl group, with a proviso that Y is other than the group ##STR4## when A means the group --CH═CH--, their preparation process and platelet aggregation inhibitors containing same.
Description
This invention relates to novel aminomethyl derivatives, and more specifically to aminomethyl derivatives having strong platelet aggregation inhibitory effects and their acid addition salts, and preparation process thereof as well as platelet aggregation inhibitors containing same.
The present inventors have synthesized a variety of compounds and investigated their pharmacological effects. In the course of the investigation, it has been found that certain specific aminomethyl derivatives have excellent platelet aggregation inhibitory effects and are hence useful for thrombus-inducing diseases of circulatory organs, leading to completion of this invention.
Accordingly, the first object of this invention is to provide an aminomethyl derivative of the following general formula (I): ##STR5## wherein A represents a group --C.tbd.C-- or --CH═CH--, Y represents a group ##STR6## (in which R3 being a lower alkyl or alkoxy group or a halogen atom) or ##STR7## (in which R4 being a hydrogen atom or R3), and R1 and R2 represent individually a lower alkyl group, with a proviso that Y is other than the group ##STR8## when A means the group --CH═CH--.
The second object of this invention is to provide a process for preparing the aminomethyl derivative represented by the general formula (I).
Furthermore, the third object of this invention is to provide a platelet aggregation inhibitor comprising the aminomethyl derivative.
The novel aminomethyl derivatives (I) of this invention may be divided roughly into the following two groups of compounds (Ia) and (Ib): ##STR9## wherein A, R1, R2, R3 and R4 have the same meanings as defined above.
Of these, the compounds of the formula (Ia) are derivatives of the so-called butynophenone. Reported earlier work on such butynophenone derivatives is limited to compounds of the above general formula (I) in which R3 is a hydrogen atom and R1 and R2 mean individually an ethyl group [Zh. Org. Khim. 11, 2311-5 (1975)]. However, their pharmacological effects have not been known to all to date.
The compounds represented by the general formula (Ia) may, for example, be prepared in accordance with the below-described reaction scheme. Incidentally, it is also possible to prepare, in the same manner, the above-mentioned compounds of the general formula (Ia) in which R3 represents a hydrogen atom and R1 and R2 represents individually a lower alkyl group which may include an ethyl group. ##STR10## wherein X represents a magnesium halide or alkali metal, and R1, R2 and R3 have the same meaning as defined above.
Namely, the intended aminomethyl derivative (Ia) is prepared by reacting a benzaldehyde derivative represented by the general formula (II) with a metal compound of propargyl amine derivative represented by the general formula (III) or reacting an α-phenyl propargyl alcohol derivativere presented by the general formula (IV) with formaldehyde and a secondary amine derivative represented by the general formula (V) to obtain an alkynolamine derivative represented by the general formula (VI) and then oxidizing the alkynol amine derivative with an oxidizing agent such as manganese dioxide or the like.
The reaction for obtaining the compound (VI) from the compound (II) and the compound (III) may be practiced by stirring, at room temperature, the compound (II) and compound (III) or causing them to reflux for several hours in a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran or the like may be employed.
On the other hand, the reaction for obtaining the compound (VI) from the compound (IV), formaldehyde and the compound (V) is the so-called Mannich reaction. This reaction may be practiced by mixing the above starting raw materials and then stirring the resultant mixture for several hours in the range of from room temperature to 60°-70° C. As a solvent for the reaction, may be employed water, methanol, ethanol, dioxane or the like.
The thus-obtained compound (VI) is further subjected to an oxidation reaction, thereby obtaining the intended compound (Ia). The oxidation may be effected by a method known per se in the art. For example, it may be effected by adding the compound (VI) and an oxidizing agent such as manganese dioxide or the like to a solvent inert to the reaction, such as methylene chloride, chloroform, carbon tetrachloride, acetone, benzene or the like and then mixing them at room temperature for several hours.
Turning to the compounds represented by the formula (Ib), they may be prepared, for example, in accordance with the following reaction equation: ##STR11## wherein R1, R2, R4 and A have the same meaning as defined above. Namely, the intended aminomethyl derivative (Ib) may be prepared by reacting an alkynolamine or alkenolamine represented by the general formula (VII) with nicotinic acid (VIII) or its reactive derivative.
As the reactive derivative of nicotinic acid (VIII), may be mentioned for example an acid halogenide, acid anhydride, mixed acid anhydride, ester or the like. When such a reactive derivative of nicotinic acid (VIII) is used, it is preferred to conduct the reaction in the presence of pyridine, a tertiary amine such as trimethylamine or triethylamine, or an deoxidizer such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide or sodium hydroxide. This reaction may be practiced by stirring, at room temperature, the reactants or causing them to reflux for several hours in a suitable solvent, for example in a solvent inert to the reaction such as tetrahydrofuran, benzene, toluene, acetone or methyl ethyl ketone. When the alkanolamine or alkenolamine represented by the general formula (VII) is reacted directly with nicotinic acid (VIII), it is preferred to use a condensing agent. For example, it is preferred to conduct the reaction in the presence of a 2-halo-1-alkylpyridinium salt and pyridine or a tertiary amine such as triethylamine or tributylamine, or in the presence of diethyl azodicarboxylate and triphenylphosphine as condensing agents. It is preferred to conduct this reaction in a solvent inert to the reaction. As such a solvent, may be mentioned ether, tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, or the like.
The thus-obtained aminomethyl derivative (I) of this invention may be converted, if necessary, into an inorganic salt such as hydrochloride, hydrobromide or sulfate or an organic salt such as maleate, fumarate, tartrate, citrate or methanesulfonate.
By the way, when A means a group --CH═CH-- in the compound (I) of this invention, the compound (I) contains both cis- and trans-isomers. Both of these isomers are included in the present invention.
The platelet aggregation inhibitory effects of the thus-obtained compounds of this invention were tested. Test results are as follows:
Platelet Aggregation Inhibitory Effects 1:
Blood, which had been added with sodium citrate, was collected from a male rabbit (body weight: 3 Kg), which was then subjected suitably to centrifugation so that platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained. Inhibitory effects of certain sample compounds of this invention against aggregation by ADP (3 μM) and arachidonic acid (1 mM) were thereafter tested by a method known per se in the art. Each sample compound was dissolved in 5% dimethylsulfoxide (DMSO) and Tween 80 (trade mark) and was then added to PRP 2 minutes before addition of each of the aggregation agents to the PRP.
Test results are shown in Table 1.
TABLE 1
______________________________________
50% Platelet Aggregation Inhibitory
Concentration (IC.sub.50) [μg/ml]
Platelet aggrega-
tion agent
Sample compound of formula (Ia)
Arachidonic
R.sub.3 R.sub.1
R.sub.2 ADP acid
______________________________________
4-CH.sub.3 C.sub.2 H.sub.5
C.sub.2 H.sub.5
7.0 2.5
4-OCH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
9.0 3.6
-- CH.sub.3
CH.sub.3 21.0 4.7
-- C.sub.2 H.sub.5
C.sub.2 H.sub.5
20.0 4.5
-- C.sub.2 H.sub.5
C.sub.3 H.sub.7
18.0 4.3
______________________________________
As apparent from Table 1, the compounds of this invention exhibited strong inhibitory effects against aggregation of platelets by ADP and against aggregation of platelets by arachidonic acid.
Platelet Aggregation Inhibitory Effects 2:
Each sample compound was orally administered at 30 mg/Kg to a male Wister rat (body weight: 220 g) which had fasted for 24 hours. Platelet-rich plasma was obtained from blood which had been collected 2 hours after the administration and added with sodium citrate. Changes in platelet aggregation upon addition of 60 μM of ADP or 100 μg/ml of collagen were observed. The number of platelets was adjusted to 6×105 platelets/mm3 for aggregation by ADP and to 3×105 platelets/mm3 for aggregation by collagen. Each of the sample compounds was dissolved in DMSO+Tween 80 (trade mark) prior to its administration. Test results are given in Table 2.
TABLE 2
______________________________________
Percent inhi-
Percent inhi-
bition against
bition against
Sample compounds of formula (Ib)
aggregation
aggregation
R.sub.4
R.sub.1
R.sub.2
A ADP collagen
______________________________________
4-CH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
20.1 37.6
4-CH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--CH═CH--
30.5 31.5
(trans)
______________________________________
As clearly envisaged form Table 2, the compounds of this invention showed strong inhibitory effects against aggregation of platelets by ADP and against aggregation of platelets by collagen.
Acute Toxicity:
Each of certain sample compounds (which had been obtained in Examples 6, 7, 10 and 15-17, which will be given herein) was dissolved in water and was then administered intraperitoneally at a dose of 200 mg/Kg to a group of five ddY male mice. Those mice were fed for 7 days while observing them. Even after the elapsed time of 7 days, all the mice were still alive and no abnormality was observed thereon. Therefore, the LD50 of each of the sample compounds is greater than 200 mg/Kg.
The aminomethyl derivatives (I) of this invention may be administered either orally or parenterally. The platelet aggregation inhibitors of this invention may be formed into various preparation forms depending on their ways of administration, for example, into orally-dosable preparation forms such as powders, tablets, capsules, granules, liquid preparations and the like; and parenterally-dosable preparation forms such as subcutaneously-injectable solutions, intramuscularly-injectable solutions and intravenously-injectable solutions, preparations suitable for admixture with transfusional solutions, ointments, tinctures, plasters, suppositories, etc.
The above formation into dosable preparation forms may be carried out by methods known per se in the art. Namely, the aminomethyl derivatives (I) may be combined and processed suitably with an excipient such as starch, lactose, mannitol or the like; a binder such as sodium carboxymethyl cellulose, hydroxypropyl cellulose or the like; a disintegrator such as crystalline cellulose, calcium carboxymethyl cellulose or the like; a lubricant such as talc, magnesium stearate or the like; a fluidity improver such as light silicic anhydride; and/or the like, thereby to produce powders, tablets, capsules or granules.
Making use of the fact that salts of the aminomethyl derivatives (I) of this invention, for example, their hydrochlorides are soluble in aqueous solvents such as water, physiological saline and the like, it is possible to produce aqueous liquid preparations, injectable aqueous preparations, etc.
For the preparation of suppositories, it is necessary to disperse the aminomethyl derivatives (I) in a usual base material, for example, cacao butter, synthetic oil and fat or the like and then to solidify the resultant dispersion.
Although subject to variations depending on the seriousness of diseases, the thus-prepared platelet aggregation inhibitors of this invention may be administered to adults, generally, at daily doses of 0.02-100 mg/Kg in terms of their aminomethyl derivatives (I) when administered orally or at doses of 0.01-50 mg/Kg in terms of their aminomethyl derivatives (I) when administered perenterally. It is suitable to administer these doses by dividing them into 1 to several portions a day.
Since the aminomethyl derivatives (I) of this invention have excellent platelet aggregation inhibitory effects and their safety levels are also high, they are effective, as platelet aggregation inhibitors, for the treatment and prevention of various diseases induced by the formation of thrombi, for example, venous thrombosis, coronary thrombosis in cardiac infarction, pulmonary embolism, cerebral thrombosis and embolism, etc.
The present invention will hereinafter be described further by the following Examples.
Dissolved in 35 ml of chloroform was 0.58 g of N-[4-(p-methylphenyl)-4-hydroxy-2-butynyl]-N,N-diethylamine. After adding 6.52 g of manganese dioxide with ice-cooling and stirring, the resultant mixture was stirred at room temperature for 3 hours. The resultant inorganic matter was filtered off and the solvent was distilled off under reduced pressure to obtain 0.53 g of the intended product as a light yellowish oily substance (yield: 92.5%).
NMR δppm (CDCl3): 8.0(d, 2H), 7.25(d, 2H), 3.7(s, 2H), 2.7(q, 4H), 2.4(s, 3H), 1.1(t, 6H).
IR νmax neat cm-1 : 2230, 1645.
The above oily substance was dissolved in anhydrous ether, to which HCl-containing ethanol was added dropwise with ice-cooling. Deposited hydrochloride salt of the title compound consisting of light yellowish crystals was collected.
Melting point: 115°-117° C.
Compounds given in Table 3 were obtained in the same manner as in Example 1.
TABLE 3
__________________________________________________________________________
Formula (Ia) m.p. (°C.)
Example
R.sub.3
R.sub.1
R.sub.2
NMR δ ppm (CDCl.sub.3)
IRυ .sub.max.sup.neat
(--HCl)-1
__________________________________________________________________________
1 4-CH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0 (d,2H), 7.25 (d,2H), 3.7 (s,2H),
2230, 1645
115-117
2.7 (q,4H), 2.4 (s,3H), 1.1 (t,6H)
2 4-C.sub.2 H.sub.5
C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0 (d,2H), 7.25 (d,2H), 3.7 (s,2H),
2240, 1640
107-109
2.0-3.0 (m,6H), 1.25 (t,3H),
1.1 (t,6H)
3 4-i-C.sub.3 H.sub.7
C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0 (d,2H), 7.25 (d,2H), 3.7 (s,2H),
2240, 1640
92-94
2.4-3.1 (m,5H), 0.9-1.5 (m,12H)
4 4-CH.sub.3 O
C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0 (d,2H), 6.85 (d,2H), 3.8 (s,3H),
2240, 1650
128-130
3.65 (s,2H), 2.7 (q,4H), 1.1 (t,6H)
5 4-Cl C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0 (d,2H), 7.4 (d,2H), 3.7 (s,2H),
2230, 1640
95-97
2.65 (q,4H), 1.1 (t,6H)
__________________________________________________________________________
Dissolved in anhydrous tetrahydrofuran was 2.17 g of N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-diethylamine, followed by an addition of 4 ml of pyridine. Then, 1.78 g of nicotinyl chloride hydrochloride was added at room temperature little by little. The resultant mixture was thereafter reacted at the same temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was taken up in chloroform. The resultant chloroform solution was washed with water and was then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain 1.5 g of the intended product as a light yellowish oily substance (yield: 46.6%).
Elemental analysis: Calculated for C20 H22 N2 O2 : C, 74.51; H, 6.88; N, 8.69. Found: C, 74.58; H, 6.92; N, 8.59.
Compound Nos. 7-14 given in Table 4 were obtained in the same manner as in Example 6.
TABLE 4
__________________________________________________________________________
Formula (Ib)
Example
R.sub.4
R.sub.1
R.sub.2
A NMR δ ppm (CDCl.sub.3)
Appearance
__________________________________________________________________________
6 H C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.1 (d,1H), 8.6 (d.d,1H), 8.2 (m,1H),
Light yellowish
7.1-7.7 (m,6H), 6.6 (m,1H),
oily substance
3.5 (m,2H), 2.6 (q,4H), 1.05 (t,6H)
7 p-CH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.15 (d,1H), 8.7 (d.d,1H),
Light yellowish
8.2 (m,1H), 7.4 (d,2H), 7.3 (m,1H),
crystals
7.2 (d,2H), 6.7 (m,1H), 3.5 (m,1H),
(m.p. 54-56° C.)
2.55 (q,4H), 2.3 (s,3H), 1.05 (t,6H)
8 p-C.sub.2 H.sub.5
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.31 (d,1H), 8.83 (d.d,1H),
Light yellowish
8.38 (m,1H), 7.63 (d,2H),
oily substance
7.33 (d,2H), 7.28 (m,1H),
6.80 (m,1H), 3.58 (m,2H), 2.60 (q,6H)
1.25 (t,3H), 1.08 (t,6H)
9 p-C.sub.3 H .sub.7--i
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.1 (d,1H), 8.62 (d.d,1H),
Light yellowish
8.18 (m,1H), 7.47 (d,2H),
oily substance
7.31 (m,1H), 7.21 (d,2H),
6.70 (m,1H), 3.5 (m,2H),
2.4-3.2 (m,1H), 2.55 (q,4H),
1.25 (d,6H), 1.04 (t,6H)
10 p-OCH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.2 (d,1H), 8.7 (d.d,1H),
Light yellowish
8.2 (m,1H), 7.4 (d,2H), 7.3 (m,1H),
oily substance
6.9 (d,1H), 6.7 (m,1H), 3.8 (s,3H),
3.5 (m,2H), 2.6 (q,6H), 1.05 (t,6H)
11 p-Cl C.sub.2 H.sub.5
C.sub.2 H.sub.5
--C.tbd.C--
9.2 (d,1H), 8.6 (d.d,1H), 8.2 (m,1H),
Light yellowish
7.0-7.6 (m,5H), 6.7 (m,1H),
oily substance
3.5 (m,2H), 2.6 (q,4H), 1.05 (t,6H)
12 H C.sub.2 H.sub.5
C.sub.2 H.sub.5
--CH═CH--
9.2 (d,1H), 8.7 (d.d,1H), 8.3 (m,1H),
Light yellowish
(trans)
7.0-7.6 (m,6H), 6.5 (m,1H),
oily substance
5.9 (m,2H), 3.1 (m,2H), 2.5 (q,4H),
1.0 (t,6H)
13 p-CH.sub.3
C.sub.2 H.sub.5
C.sub.2 H.sub.5
--CH═CH--
9.2 (d,1H), 8.7 (d.d,1H), 8.3 (m,1H),
Light yellowish
(trans)
7.0-7.6 (m,5H), 6.5 (m,1H),
oily substance
5.9 (m,2H), 3.1 (m,2H), 2.5 (q,4H),
2.3 (s,3H), 1.0 (t,6H)
14 p-Cl C.sub.2 H.sub.5
C.sub.2 H.sub.5
--CH═CH--
9.2 (d,1H), 8.7 (d.d,1H), 8.3 (m,1H)
Light yellowish
(trans)
7.0-7.6 (m,5H), 6.5 (m,1H),
oily substance
5.9 (m,2H), 3.1 (m,2H), 2.5 (q,4H),
1.0 (t,6H)
__________________________________________________________________________
Dissolved in 50 ml of chloroform was 1.13 g of N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-dimethylamine. After adding with ice-cooling and stirring 18 g of manganese dioxide to the resultant solution, the mixture was stirred at room temperature for 3 hours. After filtering off the resultant inorganic matter, the solvent was distilled off under reduced pressure to obtain 1 g of the intended product as a light yellowish oily substance (yield: 89.1%).
The above oily substance was dissolved in anhydrous ether, to which HCl-containing ethanol was added dropwise with ice-cooling and stirring. Deposited hydrochloride salt of the title compound was collected as light yellowish crystals by filtration.
Melting point: 102°-103° C.
Dissolved in 100 ml of chloroform was 2.32 g of N-(4-phenyl-4-hydroxy-2-butynyl)-N-ethyl-N-n-propylamine. After adding with ice-cooling and stirring 25 g of manganese dioxide to the resultant solution, the mixture was stirred at room temperature for 5 hours. After filtering off the resultant inorganic matter, the solvent was distilled off under reduced pressure to obtain 1.8 g of the intended product as a light yellowish oily substance (yield: 78.6%).
The above oily substance was dissolved in anhydrous ether, to which HCl-containing ethanol was added dropwise with ice-cooling and stirring to obtain the hydrochloride salt of the title compound as light yellowish crystals.
Melting point: 103°-105° C.
Following the procedure of Example 15 or 16, were obtained compounds shown in Table 5.
TABLE 5
__________________________________________________________________________
Formula (Ia) m.p. (°C.)
Example
R.sub.3
R.sub.1
R.sub.2
NMR δ ppm IRυ .sub.max.sup.neat
(--HCl)-1
__________________________________________________________________________
15 --
CH.sub.3
CH.sub.3
8.0-8.3 (m,2H), 7.2-7.7 (m,3H),
2240, 1640
102-103
3.5 (s,2H), 2.4 (s,6H)
17 --
C.sub.2 H.sub.5
C.sub.2 H.sub.5
8.0-8.3 (m,2H), 7.2-7.7 (m,3H),
2240, 1640
131-132
3,7 (s,2H), 2.7 (q,4H), 1.1 (t,6H)
16 --
C.sub.2 H.sub.5
C.sub.3 H.sub.7
8.0-8.3 (m,2H), 7.2-7.7 (m,3H),
2240, 1640
103-105
3.7 (s,2H), 2.4-2.9 (m,4H),
1.2-2.0 (m,2H), 1.1 (t,3H),
0.9 (t,3H)
__________________________________________________________________________
In a manner known per se in the art, a tablet of the following compositions (1) and (2) were prepared.
______________________________________
(1) Aminomethyl derivative 20 mg
(obtained in Example 16)
Light silicic anhydride 20 mg
Crystalline cellulose 10 mg
Hydroxypropyl cellulose 5 mg
Calcium carboxymethyl cellulose
10 mg
Talc 2 mg
Magnesium stearate 1 mg
______________________________________
The total weight was adjusted to 200 mg with lactose.
______________________________________
(2) Aminomethyl derivative 25 mg
(obtained in Example 7)
Light silicic anhydride 20 mg
Crystalline cellulose 10 mg
Hydroxypropyl cellulose 5 mg
Calcium carboxymethyl cellulose
10 mg
Talc 2 mg
Magnesium Stearate 1 mg
______________________________________
The total weight was adjusted to 205 mg with lactose.
In a manner known per se in the art, an injectable preparation was produced with the following composition.
______________________________________
Aminomethyl derivative
20 mg
(obtained in Example 16)
Physiological saline
balance to
2 ml
______________________________________
In a manner known per se in the art, granules of the following composition were prepared and they were filled in a capsule.
______________________________________ Aminomethyl derivative 20 mg (obtained in Example 1) Light silicic anhydride 17 mg Crystalline cellulose 7 mg Magnesium stearate 1 mg ______________________________________
Total weight was adjusted to 180 mg with lactose.
In a manner known per se in the art, a suppository of the following composition was prepared.
______________________________________ Aminomethyl derivative 20 mg (obtained in Example 7) Cacao butter 1180 mg Total amount 1200 mg ______________________________________
Claims (4)
1. An aminomethyl derivative of the formula: ##STR12## wherein A is selected from the group consisting of --C.tbd.C-- and --CH═CH--, Y is the group ##STR13## wherein R4 is a hydrogen atom, a halogen atom, a lower alkyl or alkoxy group, and R1 and R2 are, individually, a lower alkyl group.
2. A platelet aggregation inhibitor comprising an effective amount of an aminomethyl derivative of the formula: ##STR14## wherein A is selected from the group consisting of --C.tbd.C-- and --CH═CH--, Y is the group ##STR15## wherein R4 is a hydrogen atom, a halogen atom, a lower alkyl or alkoxy group, and R1 and R2 are, individually, a lower alkyl group; and
a pharmaceutically acceptable carrier or excipient.
3. A platelet aggregation inhibitor according to claim 2, wherein the inhibitor is in an orally-dosable form.
4. A platelet aggregation inhibitor according to claim 2, wherein the inhibitor is in a parenterally-dosable form.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13270784A JPS6112665A (en) | 1984-06-27 | 1984-06-27 | Novel nicotinic acid ester derivative |
| JP59-132708 | 1984-06-27 | ||
| JP59-132707 | 1984-06-27 | ||
| JP13270884A JPS6112652A (en) | 1984-06-27 | 1984-06-27 | Novel butinophenone derivative |
| JP59-200190 | 1984-09-25 | ||
| JP20019084A JPS6178722A (en) | 1984-09-25 | 1984-09-25 | Thrombocyte coagulation inhibiting agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4728659A true US4728659A (en) | 1988-03-01 |
Family
ID=27316560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/748,686 Expired - Fee Related US4728659A (en) | 1984-06-27 | 1985-06-25 | Aminomethyl derivatives and preparation process thereof as well as platelet aggregation inhibitors containing same |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US4728659A (en) |
| EP (1) | EP0169400A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW312688B (en) * | 1993-08-02 | 1997-08-11 | Mitsubishi Chem Corp |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2539801A (en) * | 1949-07-02 | 1951-01-30 | Rohm & Haas | Phenyl-oxo-aminoalkynes |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE792906A (en) * | 1971-12-18 | 1973-06-18 | Sumitomo Chemical Co | ARYL-KETONES AND THEIR PREPARATION |
| GB2012749B (en) * | 1979-01-11 | 1982-12-22 | Sumitomo Chemical Co | Conjugated ketones |
-
1985
- 1985-06-25 US US06/748,686 patent/US4728659A/en not_active Expired - Fee Related
- 1985-06-26 EP EP85107917A patent/EP0169400A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2539801A (en) * | 1949-07-02 | 1951-01-30 | Rohm & Haas | Phenyl-oxo-aminoalkynes |
Non-Patent Citations (4)
| Title |
|---|
| Chemical Abstracts, vol. 68, No. 16, Apr. 15, 1968, p. 7482, No. 77634w, Columbus, Ohio, US; N. M. Libman et al.: "Amino Alcohols of the Acetrylenic Series. VI." & Zh. Org. Khim. 4(1), 20-5 (1968). |
| Chemical Abstracts, vol. 68, No. 16, Apr. 15, 1968, p. 7482, No. 77634w, Columbus, Ohio, US; N. M. Libman et al.: Amino Alcohols of the Acetrylenic Series. VI. & Zh. Org. Khim. 4(1), 20 5 (1968). * |
| Chemical Abstracts, vol. 84, No. 7, Feb. 16, 1976, p. 445, No. 43543f, Columbus, Ohio, US; L. I. Vereshchagin et al.: "Addition of Alcohols and Amines to Acetylenic Amino- and Brokomoketones" & Zh. Org. Khim. 1975, 11(11), 2311-15. |
| Chemical Abstracts, vol. 84, No. 7, Feb. 16, 1976, p. 445, No. 43543f, Columbus, Ohio, US; L. I. Vereshchagin et al.: Addition of Alcohols and Amines to Acetylenic Amino and Brokomoketones & Zh. Org. Khim. 1975, 11(11), 2311 15. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0169400A1 (en) | 1986-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU621559B2 (en) | Piperidine-tetra hydrofurane or tetra hydrothiophene spiro derivatives and methods for their preparation | |
| US4868331A (en) | Substituted amino-5,6,7,8-tetrahydronaphthyl-oxyacetic acids, processes for their preparation and their use as medicaments | |
| CZ25497A3 (en) | Benzoxazoles and pyridine derivatives usable for treating type ii diabetes | |
| CZ287168B6 (en) | Process for preparing 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2 esters and intermediates for this preparation process | |
| DK157545B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 4-PHENYL-1-HYDROXYALKYLIMIDAZOLD DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. | |
| US4224342A (en) | Guanidinobenzoic acid compounds and process for preparing the same | |
| US4857644A (en) | Aryl sulfonopiperazines as anti-inflammatory agents | |
| US4031222A (en) | Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs | |
| CH637934A5 (en) | METHOD FOR PRODUCING NEW DERIVATIVES OF PERHYDRO-AZA-HETEROCYCLEN. | |
| US4791104A (en) | Dihydrobenzothiophene and thiochromane aminoalcohols | |
| FR2512820A1 (en) | NOVEL BENZOTHIAZOLINE DERIVATIVES USEFUL AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION | |
| EP0149419B1 (en) | Acylindole derivatives and pharmaceutical compositions containing them | |
| US4728659A (en) | Aminomethyl derivatives and preparation process thereof as well as platelet aggregation inhibitors containing same | |
| US4397855A (en) | 4-(Substituted)-α, α-dimethyl-1-piperazine pentanoic acids and derivatives as anti-arteriosclerotic agents and method | |
| US4109088A (en) | 2-(indenyloxymethyl) morpholine derivatives | |
| US4138407A (en) | 2,4 Pyrrolidinediones | |
| FR2522000A1 (en) | NOVEL THIOPYRANNOPYRIMIDINES, PARTICULARLY USEFUL AS HYPOGLYCEMIC AGENTS, AND THEIR MANUFACTURE | |
| US4219560A (en) | Piperidine and pyrrolidine alcohols | |
| US4552765A (en) | Aletheine derivatives | |
| US4920222A (en) | Preparation of 3,3-diarylacrylic acid amides | |
| US4262008A (en) | 2,4-Disubstituted 5-oxo-5H-hexahydrofuro[3,2b]pyrroles | |
| US4031223A (en) | Trifluoromethylthio derivatives of cyproheptadine | |
| EP0578847A1 (en) | Fused benzeneoxyacetic acid derivatives and their use as PG12 antagonists | |
| US5081152A (en) | Azulene derivatives as thromboxane a2 and prostaglandin endoperoxide receptor antagonist | |
| US4259334A (en) | Piperazines and therapeutic utility |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: SS PHARMACEUTICAL CO., LTD., 2-12-4, NIHONBASHIHAM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SATO, SUSUMU;KOUDA, TADAYUKI;KATORI, TATSUHIKO;REEL/FRAME:004790/0209 Effective date: 19850709 Owner name: SS PHARMACEUTICAL CO., LTD., 2-12-4, NIHONBASHIHAM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SATO, SUSUMU;KOUDA, TADAYUKI;KATORI, TATSUHIKO;REEL/FRAME:004790/0209 Effective date: 19850709 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 19920301 |
|
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |